The proposed work is crucial pilot work for a research plan to develop new methods for screening potential antipsychotic (neuroleptic) drugs. While many such screening techniques currently exist, they tend to identify drugs with similar pharmacological properties to those already in use. Since almost all neuroleptics in clinical use produce significant extrapyramidal side effects (EPS) and tardive dyskinesia (TD), current screening techniques tend to produce new agents with similar propensity for producing these crippling neurological side effects. In contrast, the presently proposed work emphasizes drug actions in neurobehavioral model systems that correlate with low EPS and TD, and thus may serve to identify fundamentally new therapeutic agents. The proposed pilot work constitutes an extension of our previous work, in which we have shown that the "atypical" neuroleptic clozapine (which produces little or no EPS and TD) significantly influences mesolimbic-mediate dopaminergic (DA) stereotypy and mesolimbic-mediated DA electrical intracranial self-stimulation (ICSS). However, clozapine is extremely weak in other measures of brain DA blockade. This suggests to us that "atypical" neuroleptics (those producing little or no EPS or TD) may possess functional mesolimbic specificity as compared to "classical" neuroleptics (those producing significant EPS and TD). If true, this would provide both an explanatory framework for understanding clinical drug effects and a new means for screening drugs that may constitute a significant advance in psychiatric drug development. We now seek funds for pilot work to specifically compare the effects of clozapine on mesolimbic DA ICSS vs. nigrostriatal DA ICSS. The experimental paradigm is that of drug-induced functional DA hypersensitivity as assessed by the ICSS model. If, as we hypothesize on the basis of our previous findings with DA stereotypy, a clear difference emerges in this pilot work between clozapine's effects on mesolimbic vs. nigrostriatal DA mechanisms, a large multi-faceted project (to include biochemical as well as neurobehavioral approaches) on "atypical" and "classical" neuroleptics will be proposed thru the regular NIMH grant application process. But at this point it seems prudent to pursue this limited pilot project first to see if our fundamental hypothesis is correct and worthy of further pursuit. The health-relatedness of this work is clear and straighforward - development of better drugs for the treatment of mental illness.